Title:  Methods and compositions for improving sleep

United States Patent:  6,586,478

Issued:  July 1, 2003

Inventors:  Ackman; C. Bruce (Kingston, CA); Adams; Michael A. (Kingston, CA); Heaton; Jeremy P. W. (Gananoque, CA); Ratz; Jodan D. (Kingston, CA)

Assignee:  Cellegy Canada (Kingston, CA)

Appl. No.:  791127

Filed:  February 22, 2001

Abstract

Methods and compositions for improving sleep in individuals with sleep disorders or other conditions which interfere with normal sleep via administration of a NO-mimetic are provided.

DETAILED DESCRIPTION OF THE INVENTION

The symptoms in an individual with a sleep disorder or a condition which leads to interrupted sleep manifest themselves through an individual's sensory perception and result from what is believed to be a common underlying neurogenic pathway. It is believed that the inability to sleep experienced by those individuals suffering from sleep disorders and/or conditions which interfere with sleep may be linked to changes in the nitric oxide-cyclic GMP signaling mechanisms within the peripheral and central nervous system as well nitric oxide mechanisms which are independent of cyclic GMP. Further, it is believed that the some symptoms of sleep disorders or other sleep interfering condition are brought on when the neuronal environment or functioning is altered such that cyclic GMP levels are decreased. Nitric oxide is known to signal cGMP in the peripheral nerves (Aoki E. et al. Brain Res. 1993; 620:142-145). It has now been found that NO-mimetics improve sleep via, what is believed to be, action of the NO-mimetic on cyclic GMP dependent pathway and/or pathways independent of cyclic GMP.

The present invention relates to methods for improving sleep in individuals suffering from a sleep disorder or other condition which interferes with or interrupts sleep via administration of a NO-mimetic administered either alone or in combination with additional NO-mimetics or an established drug for sleep disorders. When the NO-mimetic is administered in combination with an established drug for sleep disorders, it is expected that lower doses of the established drug than normally recommended can be used to improve sleep, thereby eliminating many of the unwanted side effects which have been reported for these known treatments. Accordingly, the present invention also provides methods for decreasing the therapeutic dosage of an established drug for sleep disorders or a condition wherein normal sleep is interrupted or interfered with by co-administering the established drug with a NO-mimetic. By co-administer it is meant that the established drug is administered at the same time, just prior to, or just after administration of a NO-mimetic. In one embodiment of the present invention, a single pharmaceutical composition is provided which comprises an established drug for sleep disorders and conditions wherein normal sleep is interrupted or interfered with and a NO-mimetic. Well known methods for formulation such as those described herein can be used to prepares these pharmaceutical compositions. Examples of established drugs for sleep disorders and conditions wherein normal sleep is interrupted or interfered with which can be used in the methods and pharmaceutical compositions of the present invention include, but are not limited to, hypnotics, sedatives and anxiolytics such as the benzodiazepines diazepam and temazepam, zoldipem, antihistamines such as NYTOL and SOMINEX, sedative antidepressants such as amitriptyline and trazodone, dopaminergic agents such as levodopa/carbidopa, bromocriptine mesylate and pergolide, and opioids such as codeine, propoxyphene, oxycodone, pentazocrine, hydrocodone, and methadone.

The methods and compositions are believed to provide relief to an individual suffering from a sleep disorder or a condition which interferes with normal sleep by replacing the deficit in endogenous NO and/or enhancing endogenous neuronal pathways for generating NO or cyclic GMP. Unlike agents currently used to induce sleep such as the sedative hypnotics, the present invention improves sleep by conditioning the neuronal micro-environment in an individual such that their ability to get to sleep and maintain a restful sleep is greatly enhanced. Small, regulatory doses of a NO-mimetic such as nitroglycerin to a patient with a sleep disorder or a condition which leads to interrupted sleep have now been demonstrated to be sufficient to restore the levels of nitric oxide in the nerves to normal levels and decrease the patient's perception of his or her sleep disorder symptoms. The net effect of the NO-mimetic agents which can be used to improve sleep in individuals with sleep disorders or other conditions which interfere with sleep is to act as neuronal conditioners which either directly or indirectly inhibit the action of nerves responsible for generating the characteristic set of symptoms of sleeplessness. While experiments described herein involve use of the NO-mimetic nitroglycerin, it is believed that any NO-mimetic that can alter the action of these nerves can be used to improve sleep in individuals suffering from sleep disorders or other conditions which interfere with sleep. Administration of any NO-mimetic, either alone or in combination with another NO-mimetic or an established drug for treatment of sleep disorders, provides relief of sleeplessness associated with sleep disorders and other conditions wherein sleep is interrupted by maintaining normalized physiological functioning in the nerves responsible for the sleeplessness. As a result, administration of a NO-mimetic prevents the symptoms of the sleep disorder or other condition which interferes with sleep, and is useful in treating sleeplessness associated with sleep disorders and other conditions which interfere with sleep and preventing individuals suffering from such disorders or conditions from perceiving sleep disorder symptoms. Also, unlike agents currently used in the treatment of sleep disorders, the use of low doses of a NO-mimetic are not habit forming or addictive and possibly leave the user feeling more alert upon waking. When the NO-mimetic is used in combination with an established drug for sleep disorders, it is believed that lower doses of the established drug than routinely prescribed can be used, thus alleviating the unwanted habit forming or addictive side effects as well as the lack of alertness upon waking associated with many of these established drugs. Accordingly, pharmaceutical compositions of the present invention which comprise a NO-mimetic and an established drug for sleep disorders and conditions wherein normal sleep is interrupted or interfered with may comprise a lower amount of established drug than routinely prescribed or administered.

The contents of all documents cited in this application are incorporated herein by reference in their entirety.

Pharmaceutical Formulations:

Pharmaceutical formulations for the administration of NO-mimetics to improve sleep in accordance with the method of the present invention may take the form of ointments, transdermal patches, transbuccal patches, injectables, nasal inhalant forms, spray forms for deep lung delivery through the mouth, orally administered ingestable tablets and capsules, and tablets or lozenges, or "lollipop" formulations for administration through the oral mucosal tissue. The latter formulations include tablets, lozenges and the like which are dissolved while being held on or under the tongue, or in the buccal pouch. It is preferred that the pharmaceutical preparations provide the desired dosage over a sustained period of time selected based upon the individual needs of a patient suffering from a sleep disorder or other condition which interferes with or interrupts normal sleep. Thus, for purposes of the present invention, a "sustained period" may range from only a few minutes up to about 12 hours and is inclusive of, but not limited to intermediary ranges such as 0.5-10, 2-8, 2-6 and 3-4 hours.

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a NO-mimetic formulated together with one or more pharmaceutically acceptable carriers. In addition to the NO-mimetic, the pharmaceutical compositions of the present invention may further comprise an established durg for sleep disorders and conditions wherein normal sleep is interrupted or interfered with. Examples of established drugs for use in these pharmaceutical compositions include, but are not limited to, hypnotics, sedatives and anxiolytics such as the benzodiazepines diazepam and temazepam, zoldipem, antihistamines such as NYTOL and SOMINEX, sedative antidepressants such as amitriptyline and trazodone, dopaminergic agents such as levodopa/carbidopa, bromocriptine mesylate and pergolide, and opioids such as codeine, propoxyphene, oxycodone, pentazocrine, hydrocodone, and methadone.

As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to an individual orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), supralingually (on the tongue) sublingually (under the tongue), bucally (held in the buccal pouch), or as an oral or nasal spray. The oral spray may be in the form of a powder or mist which is delivered to the deep lungs by oral inhalation.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In cases where it is desirable to prolong the effect of the drug, the absorption of the drug from subcutaneous or intramuscular injection can be slowed. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

A preferred mode of delivery is one which provides a reasonably steady-state delivery of therapeutic agent, so as to maintain steady-state plasma concentrations. Such delivery avoids any substantial initial spike in plasma concentration of the agent, as it would be desirable to avoid plasma concentrations that produce negative side effects. Transdermal patches and pulsed delivery systems are preferred modes of delivery.

Nitroglycerin Transdermal Patches:

A preferred formulation and dose delivery system of the present invention comprises a patch for transdermal delivery of a NO-mimetic such as nitroglycerin, isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, and erythrityl tetranitrate. A preferred NO-mimetic for transdermal patches in accordance with the present invention is nitroglycerin.

Transdermal nitroglycerin patches (MINITRAN, 3M Corporation, St. Paul, Minn., USA) were prepared in three sizes, both in forms containing nitroglycerin and drug-free placebo. The patches had a release liner, uniformly of 1 inch² (6.65 cm²), with a circular drug-containing (or placebo) patch having areas of 3.33 cm², 1.65 cm², or 0.825 cm². The various-size drug-containing patches had nitroglycerin loadings of about 2.7 mg of nitroglycerin/cm² and the total loadings shown in Table 1.

3M MINITRAN transdermal nitroglycerin patches of 10 cm² and 20 cm² areas deliver plasma levels of 102 pg/mL and between 129 pg/mL and 310 pg/mL, respectively. The 3.3 cm² patch, with a total loading of 9 mg of nitroglycerin in each patch, has a mean rate of drug delivery of about 0.81 mg/cm² /hour. The two smaller patches (1.65 cm² and 0.825 cm²) used in the studies described herein had areas of one half and one fourth the 3.33 cm² patch. Based on the ratios of patch surface area and assuming linearity in the rates of drug delivery, the estimated rates of delivery and extrapolated values of plasma levels of nitroglycerin for the three low or microdose patches are given in Table 1.

TABLE 1
           Calculated Delivery Rates and Plasma Levels
        of Nitroglycerin Delivered from Microdose Patches
       Patch Area      Delivery Rate
       (cm²)     mg/cm² /24 hours    Plasma Level (pg/mL)
           10.0            0.81               102¹
            3.33      0.63-0.81²          34³
            1.65      0.63-0.81²          17³
            0.825     0.63-0.81²           9^{3
    1} Measured; ² Estimated; ³ Extrapolated from larger-size
     patches assuming linearity.
 

The stability of low or microdose transdermal nitroglycerin patches for use in accordance with the method of the present invention is illustrated by the data appearing in Table 2.

Dosing and Administration:

In doses used for prophylaxis of acute attacks of angina pectoris and for general vasodilation, compounds which generate or release NO, such as those listed above, dilate the capacitance veins and the conductance arteries. Dilation of the capacitance veins decreases the ventricular filling pressure, while dilation of the conductance arteries decreases arterial impedance. The former effect tends to decrease cardiac output, while the latter tends to increase it with a net increase in cardiac output if serum levels of NO are maintained.

These compounds all have a common mechanism of action which involves in vivo denitration to produce NO which is also an endothelial-derived relaxing factor (EDRF) endogenously generated by the oxidation of L-arginine. NO reacts with sulfhydryl compounds in blood vessels to form adducts which stimulate guanylyl cyclase, causing smooth muscle relaxation.

In accordance with the present invention, a NO-mimetic is administered to an individual in an amount therapeutically effective to improve sleep. An effective amount can be that which is provided to induce systemic vasodilation in normal circulation in an individual. Therapeutically effective amounts of NO-mimetics that induce systemic vasodilation in normal circulation in a human are given in Table 3 under the column heading "Commercial Product". However, administration of such amounts of NO-mimetics is often associated with negative side effects of the NO-mimetics. It has been discovered in the present invention that sleep can be improved in individuals with sleep disorders by the administration of a NO-mimetic in an amount substantially smaller than that which appreciably alters systemic tone in a human or is used to manage the symptoms associated with angina or congestive heart failure, thereby largely avoiding the negative side effects of NO-mimetics. Thus, in accordance with a preferred aspect of the invention, typical "low doses" of NO-mimetics are as described in Table 3 under the column heading "Preferred Dose According to the Present Invention".

The terms "low dose" or "microdose" of a NO-mimetic are used interchangeably throughout this specification and the appended claims and mean a dose which ranges between about one half (1/2) to about one fortieth (1/40) of the dose known to appreciably alter systemic vascular tone in normal circulation in a human. This "low" or "microdose" range for the use of NO-mimetics in the present invention is derived from the observation that doses of a NO-mimetic which are below the upper end of the range, i.e. below about 1/2 the normal dose, systemic vasodilation is generally no longer seen. Doses below the low end of the range, i.e. below about 1/40 the normal dose, do not elicit the desired improvement in sleep. Accordingly, one of skill in the art can routinely select and/or determine appropriate doses of an NO-mimetic to be administered in the present invention to improve sleep based upon the teachings provided herein and upon doses of NO-mimetics established in the prior art to appreciably alter systemic vascular tone. Appropriate doses to be administered to an individual may be routinely selected based upon the teachings herein by monitoring the patient for symptoms of inappropriate systemic vasodilation such as hypotension, headache, and flushing as well as parameters as set forth herein for determining improved sleep. Appropriate doses will improve one or more parameters of sleep as set forth herein. For examples of typical preferred low-dose or microdose ranges for representative NO-mimetics, see Table 3.

Using GTN transdermal patches as an example, Table 4 compares the sizes (cm²) patches typically used in accordance with the present invention to the size (cm²) of the smallest patch currently available from 3M (3M MINITRAN patch). As can be seen from Table 4, the sizes of patches used in accordance with the present invention are about 1/2 to 1/40 the size of the smallest commercially available patch. Assuming that dosage scales linearly with patch size, the patch sizes used in the present invention provide dosages in the range of about 1/2 to 1/40 those provided by the smallest commercially available patch.

For those formulations containing a NO-mimetic which is commercially available, the low dose or microdose formulations contemplated for use in the method of the present invention are formulated according to the same methods as the commercially available higher dose formulations, but with amounts generally ranging between about 1/2 and about 1/40 of the active ingredient. Methods of formulation are within the skill of pharmaceutical formulation chemists and are fully described in such works as Remington's Pharmaceutical Science, 18^th Edition, Alfonso R. Gennaro, Ed., Mack Publishing Co., Easton, Pa., USA, 1990.

As can be seen from the data in Table 4, patches according to the invention providing about 1/8 or less of the dose of GTN known to induce systemic vasodilation are considerably small. When such small doses of NO-mimetic are desired, it is preferable to reformulate (i.e., dilute) the NO-mimetic so that a larger patch size can be used, while maintaining the required low dose. Also, since the laws of mass action are a key factor in determining delivery rates, it has also been contemplated that there is a potential that the rate of drug delivery in the smaller sized patches would not scale linearly (i.e. a patch area of 1/40 as presented in Tables 1 and 4, may deliver plasma levels of the drug at less than 1/40 the dose of the 3.3 cm² patch). As discussed above, methods of such formulation are within the skill of pharmaceutical formulation chemists and are fully described in such works as Remington's Pharmaceutical Science, 18^th Edition, Alfonso R. Gennaro, Ed., Mack Publishing Co., Easton, Pa., USA, 1990.

Claim 1 of 15 Claims

What is claimed is:

1. A method for improving sleep in an individual suffering from a sleep disorder, said method comprising administering to the individual a NO-mimetic in an amount therapeutically effective to improve sleep in the individual, where the amount of NO-mimetic administered is about one half to about one fortieth of the amount of NO-mimetic known to appreciably alter systemic vascular tone in normal circulation in a human.

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